We present the case of a 28-year-old female with no atopic or autoimmune history who reported recurrent episodes of IA since childhood. These episodes occurred up to twice weekly and consisted of acute spontaneous pruritis, urticaria, flushing, diarrhea, tachycardia, lightheadedness, and presyncope or complete syncope without a consistent pattern or trigger. Her symptoms reportedly improved acutely with the use of first or second-generation antihistamines and/or intramuscular epinephrine. She reported previously failing chronic low-dose prednisone as a prophylactic agent without trialing high doses for prolonged periods of time. She was also not interested in a trial of higher dose prednisone in an attempt to provide tighter control of her symptoms due to poor tolerance of the medication. While she did report frequent emergency department visits for her episodes, she denied ever requiring intubation, hospitalization, or admission to the intensive care unit, with symptoms often resolving after self-treatment at home. Notably, she reported using an epinephrine autoinjector on an almost weekly basis and requested frequent EpiPen refill prescriptions. She reported being otherwise generally healthy, with a previous medical history consisting primarily of mental health concerns to include anxiety, panic disorder, and PTSD for which she received active care.

She was first evaluated by an allergist for symptomatic episodes in 2019 and found to have an elevated chronic urticaria index (13.1) and normal basal serum tryptase (6.6 mcg/L) with otherwise unremarkable basic labs. She was initiated on high dose antihistamines and given EpiPens to carry. She reported no significant improvement in episode frequency or severity and was subsequently placed on maximally dosed H1 and H2 blocking antihistamines and the leukotriene antagonist, montelukast. Despite this treatment strategy, she continued to report two to three episodes monthly. After one episode that she was unable to abort with self-treatment at home, she presented to the emergency room and was found to have an urticarial rash and an acutely elevated serum tryptase of 17.2 mcg/L with an otherwise unremarkable acute workup. She was treated medically and discharged home without the need for overnight observation.

She was diagnosed by her allergist with refractory IA and frequent idiopathic urticaria and started monthly 300 mg subcutaneous injections of omalizumab in August of 2020. She stated that omalizumab significantly improved her frequency of IA and chronic urticaria. Despite this, she continued to suffer frequent IA and eventually required increased frequency of omalizumab injections to 300 mg every three weeks to more adequately control her episodes. A note written by her allergist in November of 2020 stated, “[The patient] has self-administered EpiPen on at least 5 occasions over the last 3 months.”

Because of her concerning persistent symptomatology, she underwent bone marrow biopsy to assess for a clonal mast cell disorder. Her bone marrow was noted to be normocellular, devoid of mast cell aggregates or atypical mast cell populations, and negative for D816V KIT and BCR-ABL mutations. Of note, CD25 and/or tryptase staining were not performed and Sanger sequencing was used to assess for the D816V KIT mutation. The pathologist’s bone marrow biopsy report notes stated, “Normal numbers of singly scattered CD117 + mast cells…with no aggregates, atypical morphology, or aberrant CD2 expression.”

Despite the use of 300 mg subcutaneous omalizumab every three weeks, maximum dose antihistamines, and montelukast, she continued to suffer monthly IA episodes. When her allergist retired, she found it difficult to receive continued prescriptions for omalizumab via a local civilian allergist. She presented to the Eisenhower Army Medical Center Allergy Clinic in early 2022 and reported multiple episodes per month of IA requiring frequent use of EpiPens in the context of a lack of access to omalizumab for several months.

Extensive evaluation at our clinic included normal basic labs (including CBC, CMP, TSH, ESR, and CRP), negative digital droplet polymerase chain reaction D816V KIT mutation testing on peripheral blood, normal 24-hour urine N-methylhistamine, normal TPSAB1 copy number analysis, and undetectable serum specific IgE (sIgE) to alpha-gal and omega-5-gliadin. Her total IgE was 382 mg/dL, and serum immunoglobulins, 5-HIAA, vasoactive intestinal peptide, gastrin, calcitonin, and plasma metanephrines were all within normal range. Serum sIgE to a wide array of foods and aeroallergens revealed robust sensitization to tree pollens and a food sensitization profile consistent with in vitro cross-reactivity to tree pollen (monosensitization to Cor a1 and Ara h8 on hazelnut and peanut component panels in the setting of oral tolerance to all tested foods). Notably, repeat chronic urticaria index was again elevated at 39.7.

Given her report of monthly IA episodes even when previously on omalizumab at a frequency of every three weeks, our clinic started the patient on 300 mg subcutaneous dupilumab off-label injected every two weeks in October of 2022. After dupilumab initiation, she reported one spontaneous episode of urticaria and gastrointestinal symptoms in November of 2022 but subsequently noted complete resolution of urticaria and IA. As of the time of this publication, she has been symptom free with zero IA or urticaria episodes for at least six months while on dupilumab.